📋 Browse Articles

This review aims to elucidate the molecular mechanisms underlying the neuroprotective effects of acupuncture in preclinical models of Parkinson's disease (PD). In PD animal models, acupuncture inhibits oxidative stress by upregulating nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) while reducing malondialdehyde (MDA) and lipid peroxidation. It regulates autophagy either independently of mammalian target of rapamycin (mTOR) or via mTOR activation, promoting alpha-synuclein (α-synuclein) clearance. Acupuncture also suppresses apoptosis (modulating Bcl-2-associated X protein (Bax)/B-cell lymphoma 2 (Bcl-2)) and pyroptosis (inhibiting NLR family pyrin domain containing 3 (NLRP3) inflammasome and gasdermin D (GSDMD)). It enhances neurogenesis through brain-derived neurotrophic factor (BDNF)/extracellular signal-regulated kinase (ERK)/cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) and glial cell line-derived neurotrophic factor (GDNF) signaling, promoting neural stem cell proliferation and differentiation. Furthermore, acupuncture reduces neuroinflammation by decreasing microglial activation, cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β). It also modulates gut microbiota composition (e.g., increasing butyrate-producing bacteria like Butyricimonas and reducing pro-inflammatory Erysipelotrichaceae and Bacteroides) and influences lipid metabolism, thereby mitigating dopaminergic neuron loss and motor deficits. Preclinical evidence demonstrates that acupuncture exerts multi-target neuroprotective effects against PD through pathways involving oxidative stress, autophagy, apoptosis/pyroptosis, neurogenesis, neuroinflammation, and gut microbiota-lipid metabolism crosstalk. However, limitations include a focus on preventive rather than reversal effects, lack of long-term efficacy data, and heterogeneity in acupoint selection. Further mechanistic and standardization studies are warranted. Show less

To investigate the protective effects of dexmedetomidine on cerebral ischemia-reperfusion injury through the activation of the brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) signaling pathway. This study utilized hippocampal neuronal oxygen-glucose deprivation/reoxygenation (OGD/R) models and rat middle cerebral artery occlusion models, with dexmedetomidine intervention. Compared with the sham-operated group, the model group rats exhibited a significant increase in Zea-Longa scores, a marked prolongation of the escape latency, a notable reduction in the number of platform crossings, a significant increase in the percentage of cerebral infarct size, and a marked decrease in the expression of BDNF, TrkB, and Bcl-2 proteins and mRNA (P < 0.05). The dexmedetomidine group showed significantly better outcomes in all above parameters compared to the model group. Compared with the control group, the OGD/R group exhibited a reduction in hippocampal neuronal cell viability, a significant increase in apoptosis rate, elevated expression of Bax and C-caspase-3 proteins, a marked decrease in Bcl-2 protein levels, and a significant reduction in the expression of BDNF and TrkB proteins and mRNA (P < 0.05). Dexmedetomidine exerts significant neuroprotective effects by activating the BDNF/TrkB signaling pathway, thereby alleviating ischemic brain injury. Show less

Neuropsychiatric dysfunction is increasingly being acknowledged as a disabling complication of non-alcoholic steatohepatitis (NASH), but there are no therapeutic approaches. We investigated in the present study the neuroprotective effectiveness of naringenin, a citrus flavonoid with known anti-inflammatory and neurotrophic effects, in a murine NASH model induced by an 8-week methionine-choline-deficient (MCD) diet. Male C57BL/6 mice (n = 8/group) were treated with naringenin (50 mg/kg/day, i.p.) during the final 4 weeks. In behavioral tests, naringenin counteracted cognitive impairment in novel object recognition, reduced anxiety in both open field and elevated plus maze paradigms, and decreased immobility in the forced swim test, indicating antidepressant-like activity. Mechanistically, naringenin restored hippocampal apoptotic balance, normalizing the MCD diet-induced Show less

This comprehensive review examines the synergistic effects of physical exercise and polyphenolic compounds, such as flavonoids, curcumin, and resveratrol, on spatial learning and memory. The interplay between these interventions highlights their potential to enhance cognitive function by promoting neurogenesis, synaptic plasticity, and resilience against oxidative stress and inflammation. Mechanistic insights reveal that exercise and polyphenols activate complementary neuroprotective pathways, including the upregulation of BDNF and CREB, as well as the modulation of antioxidant defenses via Nrf2. Evidence from both animal and human studies demonstrates significant improvements in spatial memory and hippocampal function when these strategies are combined. Despite promising findings, challenges related to bioavailability, dosing, and long-term efficacy remain, underscoring the need for further investigation. This review emphasizes the potential clinical applications of these combined approaches for preventing cognitive decline and promoting brain health during aging and in neurodegenerative conditions. Show less

Obesity and excessive weight gain have emerged as significant global health concerns in recent years and are often comorbid with numerous contemporary diseases, including cardiovascular disorders, diabetes, and cognitive impairments. L-carnitine, a vital cofactor in mitochondrial energy metabolism, possesses potent antioxidant and anti-inflammatory properties that merit investigation for mitigating obesity-associated neuronal damage. Consequently, this study investigated the potential neuroprotective effects of L-carnitine on anxiety- and depression-like behaviors in adolescent rats subjected to neonatal monosodium glutamate (MSG) exposure, a model known to induce obesity and associated neurobehavioral alterations. Neonatal rats received MSG (4 g/kg, s.c.) on alternate postnatal days (PND) 2-10. Subsequently, L-carnitine (200 mg/kg) was administered via oral gavage daily from PND 60 to 81 (subchronic treatment). Anxiety- and depression-like behaviors were assessed using the Forced Swim Test (FST), Elevated Plus Maze (EPM), and Open Field Test (OFT). All molecular and histological analyses were conducted in the prefrontal cortex (PFC), a region selected for its susceptibility to excitotoxicity and critical role in emotional regulation. Oxidative stress was evaluated through measurements of total oxidant and antioxidant levels. To elucidate the underlying molecular mechanisms, gene expression analyses focused on neuronal survival and apoptosis (BDNF, Bax, Bcl-2), while immunohistochemical evaluations targeted neuroinflammation and cell death pathways (TNF-α, Caspase-3, IL-1β, and Bcl-2). The findings reveal that neonatal MSG exposure leads to pronounced anxiety- and depression-like behaviors, accompanied by metabolic dysregulation, oxidative stress, neuroinflammation, and apoptosis. Although L-carnitine treatment did not reverse obesity-related metabolic alterations, it exhibited notable sustained anxiolytic effects. The neuroprotective potential of L-carnitine was further supported by its ability to reduce cortical neuroinflammation and neurodegerenative damage through suppression of proinflammatory cytokines and restoration of antioxidant balance. Overall, this study offers valuable insights into the cognitive, genetic, and histological outcomes associated with obesity-related mood disturbances and contributes to understanding the complex biological mechanisms underlying these conditions. Show less

Neuro-related disorders will be rising globally. Current treatments have numerous limitations that can impair patients' quality of life. One of the key therapeutic approaches is promoting neuroplasticity. Neuroplasticity plays a vital role in memory, learning, and recovery of function after neural damage. Acetaminophen (Paracetamol; APAP) has been suggested as a neuroprotective treatment through modulation of neuroplasticity dose-duration dependently. This systematic review was conducted across major databases such as PubMed/MEDLINE, Google Scholar, Scopus, and Web of Science, between 2002 and October 2025, and from an initial pool of 537 articles, we selected only English-language studies with complete methodology and full results reporting the effects of acetaminophen on neuroplasticity. Preclinical evidence suggests that short-term, low-dose acetaminophen can have neuroprotective effects. Acetaminophen is metabolized in the brain to AM404, which activates TRPV1, inhibit COX-1/COX-2, and modulates the endocannabinoid system, reducing inflammation and oxidative stress. They also engage BDNF neurotrophic signalling, creating a mechanistic basis for potential neuroplasticity modulation. While low-dose, short-term acetaminophen shows neuroprotective effects in preclinical models, long-term or high-dose use may lead to neurotoxicity. Although preclinical evidence suggests that acetaminophen may influence neuroplasticity in a dose- and time-dependent manner, substantial heterogeneity in dosing protocols limits definitive conclusions. Therefore, further standardized preclinical and clinical studies with larger sample sizes and longer follow-up are required to define safe and effective exposure windows in humans. Show less

Bupivacaine (BUP), a widely used amide-type local anesthetic, exhibits neurotoxic effects. This study aimed to explore the functions of brain-derived neurotrophic factor (BDNF) and methyltransferase Like 3 (METTL3) in BUP-induced hippocampal neuronal damage. HT22 cells and SH-SY5Y cells were treated with various concentrations of BUP. METTL3 and BDNF were manipulated using either overexpression or knockdown approaches to assess their functional roles. Cell viability, apoptosis, mitochondrial membrane potential and oxidative stress markers (Lactate Dehydrogenase (LDH), Reactive Oxygen Species (ROS), Superoxide Dismutase (SOD), Malondialdehyde (MDA)) were evaluated using Cell Counting Kit-8 (CCK-8), flow cytometry, JC-1 staining and commercial kits. The expression of BDNF, METTL3, Caspase-9, Bax and Bcl-2 was analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot. The N6-methyladenosine (m6A) modification of BDNF mRNA was assessed using Methylated RNA Immunoprecipitation (Me-RIP) and commercial kits. BUP treatment dose-dependently reduced viability, while increasing oxidative stress and apoptosis in our cellular model. BDNF expression was down-regulated in BUP-induced cells. Additionally, BUP stimulation suppressed both total m6A levels and METTL3 expression in cell models. Overexpression of BDNF ameliorated BUP-induced cell damage. METTL3 stabilized BDNF through m6A modification, and the depletion BDNF reversed the protective effect of overexpressing METTL3 on BUP-induced neurotoxicity. Together, our results indicated that METTL3 attenuated BUP-induced neurotoxicity by enhancing BDNF expression via m6A modification. Show less

Spinal cord injury (SCI) leads to severe sensory, motor, and autonomic dysfunction with limited treatment options. Ginsenosides, the primary bioactive compounds derived from Panax ginseng, have demonstrated neuroprotective potential in SCI. This systematic review aims to evaluate the preclinical evidence regarding the multi-target mechanisms of ginsenosides in SCI Methods: A comprehensive literature search was conducted following PRISMA guidelines across PubMed, Web of Science, and Google Scholar up to January 2025. Of the 385 identified articles, 22 studies met the inclusion criteria, which focused on the pharmacological effects of ginsenosides in SCI using both in vivo and in vitro models. Data on mechanisms, models, and outcomes were systematically synthesized Results: Ginsenosides exerted multi-target neuroprotective effects in SCI models, including antiinflammatory actions via suppression of TLR4/NF-κB and MAPK signaling, leading to reduced TNF-α, IL-1β, and IL-6, antioxidant activity through Nrf2/HO-1 pathway activation, enhancing SOD, CAT, and GSH, anti-apoptotic effects via ASK1/JNK inhibition, lowering caspase-9/3 and Bax while elevating the Bcl-2/Bax ratio, regulation of autophagy by activating PI3K/Akt to prevent excessive self-digestion, promotion of neural repair through upregulation of neurotrophic factors (NGF, bFGF, BDNF, and GDNF) and extracellular matrix components (laminin, fibronectin), inhibition of spinal cord edema via increased AQP4 expression, and facilitation of nerve regeneration by promoting astrocyte-to-neuron conversion and olfactory ensheathing cell migration Discussion: The findings highlight the synergistic mechanisms of ginsenosides in addressing key pathological processes in SCI, including inflammation, oxidative stress, apoptosis, and impaired neural regeneration. While preclinical evidence underscores their therapeutic promise, the translational potential requires validation through rigorous clinical trials to confirm efficacy, safety, and applicability in humans Conclusion: Ginsenosides exhibit multi-target neuroprotective effects in SCI models, positioning them as promising candidates for therapeutic development. Further clinical studies are essential to advance their application in SCI treatment. Show less

The prevalence of neurodegenerative disorders continues to increase with population aging. Brain-derived neurotrophic factor is a biomarker of cognitive function and neuroprotection. Lactobacillus plantarum C29-fermented soybean (DW2009) has been suggested to enhance cognition by modulating brain-derived neurotrophic factor. This secondary analysis of a randomized, double-blind, placebo-controlled trial investigated the influence of sociodemographic and lifestyle factors on serum brain-derived neurotrophic factor responsiveness to DW2009 supplementation. One hundred adults (age: 55-85 years) with mild cognitive impairment were randomized 1:1 to receive DW2009 (800 mg/day) or placebo (800 mg/day) for 12 weeks. The participants were examined, and their cognitive clinical features and serum brain-derived neurotrophic factor (BDNF) levels were measured at baseline and after a 12-week period. We found that DW2009 significantly increased serum BDNF levels, especially in older men (≥ 68 years) and in those with lower educational attainment (≤ 11 years). Subgroup analysis also indicated that the effect of DW2009 was enhanced in participants who performed frequent physical activity (≥ 5 times/week) and those within the normal body mass index range (18.5-22.9 kg/m²). Our findings suggest that the increase in serum BDNF after DW2009 supplementation is dependent on baseline characteristics, although this interpretation requires confirmation. DW2009 intake was linked to increased serum BDNF levels in individuals with specific sociodemographic and lifestyle characteristics. These findings suggest that personalized supplementation strategies may optimize functional benefits for cognitive health. Show less

Glyphosate (GLY) is a widely used herbicide, particularly in agriculture, and its residues in plants and soil can induce toxic effects in various organisms, including humans, with the brain being especially vulnerable. Eugenol (EU), a natural antioxidant found in cloves, has demonstrated protective effects against different toxic substances. This experimental study explored whether eugenol could mitigate neurological damage triggered by glyphosate exposure in rats. A total of forty male Sprague-Dawley rats were allocated into five experimental groups consisting of control, eugenol (100 mg/kg), glyphosate (150 mg/kg), EU50 combined with glyphosate (50 mg/kg + 150 mg/kg), and EU100 combined with glyphosate (100 mg/kg + 150 mg/kg). Animals received the respective treatments by oral gavage for a period of seven days. Motor and anxiety-related behaviors were evaluated using behaviour tests, after which brain tissues were processed for histopathological analysis. Biochemical analyses included ELISA assessment of oxidative stress markers (MDA, SOD1, GSH, and GPx1), RT-PCR analysis of endoplasmic reticulum (ER) stress- and apoptosis-related genes (GRP78, ATF4, CHOP, PI3K/AKT/mTOR, BAX, and Bcl-2), Western blot evaluation of inflammatory and antioxidant signaling pathways (TLR4/NF-κB and Nrf2/HO-1/SIRT1), and immunohistochemical and immunofluorescence analyses of neuroplasticity, circadian rhythm, and autophagy markers (BDNF, BMAL1, CLOCK, Beclin-1, and LC3A/B). GLY exposure significantly increased lipid peroxidation (MDA), ER stress markers (GRP78 and CHOP), pro-inflammatory mediators (TLR4, NF-κB, TNF-α, and IL-1β), apoptotic signaling (BAX and caspase-3), and autophagy-related proteins, while suppressing antioxidant pathway components. Glyphosate exposure induced behavioral impairments accompanied by increased oxidative stress, inflammatory activation, endoplasmic reticulum stress, apoptosis, and dysregulated autophagy in cerebral cortex tissue. EU treatment dose-dependently attenuated these molecular and histopathological alterations, restored antioxidant and cellular stress responses, and significantly improved behavioral performance, indicating a protective role against GLY-induced neurotoxicity. Overall, EU may represent a promising therapeutic candidate for mitigating herbicide-induced brain injury. Show less

Pulmonary fibrosis is a common and life-threatening complication of Parkinson's disease (PD), yet the molecular mechanisms linking the two diseases remain unclear, creating a critical gap in targeted therapeutic strategies for comorbid patients. Angiotensin-converting enzyme 2 (ACE2) plays a key role in neuroprotection and lung homeostasis; its deficiency exacerbates PD-related neuroinflammation and α-synuclein aggregation, while also promoting pulmonary inflammation and fibrotic remodeling. Clarifying how ACE2 deficiency drives PD-exacerbated pulmonary fibrosis is therefore an urgent unmet need. This study explored the underlying mechanisms using MPTP-induced PD mouse models and bioinformatics analyses of PD/idiopathic pulmonary fibrosis (IPF) datasets from the GEO database. In MPTP-induced PD mice, ACE2 deficiency significantly worsened motor/non-motor dysfunction, dopaminergic neuron loss, microglial/astrocytic activation, and lung fibrosis (evidenced by elevated α-SMA/TGF-β and increased collagen deposition). Bioinformatics identified 41 overlapping differentially expressed genes (DEGs) between PD and IPF, enriched in critical pathways: downregulated FoxO1 (impairing antioxidant defense) and upregulated TNF, JAK1-STAT3, and AGE-RAGE (amplifying inflammation/fibrosis). ROC analysis validated hub genes (e.g., BDNF, FOSL2) with good diagnostic value (AUC > 0.7), and molecular docking identified Smilagenin, Fostamatinib, Olopatadine, and Amlexanox as potential therapeutics. This study confirms ACE2 deficiency is a central driver of PD-exacerbated pulmonary fibrosis via the FoxO1/TNF/JAK1-STAT3/AGE-RAGE pathways, providing novel biomarkers and drug candidates to address the clinical need for managing this comorbidity. Show less

Huntington's disease (HD) is characterized by progressive striatal degeneration associated with mutant huntingtin (mHTT)-related proteostatic disruption and chronic neuroinflammation. Although mHTT-lowering approaches hold therapeutic promise, their capacity to restore the degenerating neural microenvironment remains limited. Here, we evaluated the therapeutic potential of human induced pluripotent stem cell (iPSC)-derived neural precursor cells (s513-NPCs) in two complementary HD models, the acute R6/2 transgenic fragment model and the protracted, full-length YAC128 genomic model. Intrastriatal transplantation of s513-NPCs resulted in sustained functional improvement, including stabilization of motor coordination and attenuation of neuromuscular decline, across both disease contexts. These neuroprotective effects were accompanied by efficient donor cell engraftment and integration within the host striatum. At the molecular level, transplantation was associated with coordinated changes in proteostasis-related pathways, reflected by reduced mHTT aggregate burden and modulation of proteasomal and autophagic markers. In parallel, enhanced local BDNF-TrkB signaling was observed in grafted regions, consistent with improved neuronal support. Notably, transplanted NPCs exhibited context-dependent immunological responses, characterized by attenuation of pro-inflammatory signatures in aggressive disease stages and features of a reparative microenvironment in more protracted settings. Collectively, these findings demonstrate that iPSC-derived neural precursor transplantation confers robust neuroprotective effects in HD models, supporting its potential as a stem cell-based strategy to mitigate striatal pathology and functional decline. Show less

Huangqi Guizhi Wuwu Decoction (HGWD) is a classic formula recorded in the Jin Gui Yao Lue. It is primarily used to treat symptoms of "blood stasis", such as numbness in the limbs and poor circulation, and has been widely applied clinically in the treatment of stroke. Its traditional efficacy suggests potential for promoting neurological function recovery and regulating the microenvironment. However, its mechanism in neuroprotection and functional recovery after ischemic stroke (IS) remains unclear. This study aims to elucidate the molecular mechanism by which HGWD exerts neuroprotective effects and promotes neurological recovery following IS by inducing M2 polarization of microglia through activation of the PI3K/Akt/mTOR signaling pathway. The chemical constituents of HGWD were identified using Ultra Performance Liquid Chromatography-Mass Spectrometry (UHPLC-MS). Network pharmacology was employed to predict the active components of HGWD and targets, along with potential signaling pathways. A middle cerebral artery occlusion (MCAO) in vivo model was established using Sprague-Dawley (SD) rats, whilst primary microglia were isolated to construct an oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro model. TTC staining was used to assess the volume of cerebral infarction, and neurological function was evaluated using mNSS and the rotarod test. RT-qPCR, Western blot, immunofluorescence, or flow cytometry were used to detect axonal remodeling, the PI3K/Akt/mTOR signaling pathway, and microglial polarization markers, while ELISA was used to detect inflammatory cytokines. The in vivo dosage of HGWD was 2.5 g/kg i.g. and 5 g/kg i.g., and the in vitro concentrations were 50 μg/mL and 100 μg/mL. Using LY294002 and Rapamycin as PI3K and mTOR inhibitors, we verified that HGWD promotes the recovery of neurological function after IS by activating the PI3K/Akt/mTOR signaling pathway. Network pharmacology revealed that the core components of HGWD overlap with the PI3K/Akt/mTOR signaling pathway and microglial polarization targets. HGWD significantly improved neurological function in MCAO rats, reduced cerebral infarction area, and increased neuronal survival. This formula increased the expression of GAP-43, PSD95, and BDNF, while promoting axonal remodeling and synaptic repair. HGWD inhibited the expression of M1-type markers (CD86, iNOS) and increased the expression of M2-type markers (CD206, ARG1), while ELISA showed a shift of inflammatory cytokines towards anti-inflammatory effects. In microglia, HGWD restored OGD/R-induced cell viability and promoted M2 polarization via the PI3K/Akt/mTOR signaling pathway. Both in vivo and in vitro experiments showed that HGWD significantly increased the phosphorylation levels of PI3K, Akt, and mTOR. LY294002 and rapamycin partially blocked these results, while rescue experiments using the Akt activator SC79 combined with analysis of downstream STAT3 and P65 further illustrate that this process is Akt pathway dependent. The results suggest that HGWD can exert a neuroprotective effect by activating the PI3K/Akt/mTOR signaling pathway, thereby promoting neurological function recovery. HGWD may activate the PI3K/Akt/mTOR signaling pathway, drive microglia to M2 polarization, regulate neuroinflammation, and promote neuroplasticity, thereby achieving neuroprotection and functional recovery after IS. Show less

Central pathophysiological mechanisms underlying cognitive impairment and mood disorders are complex. Traditional Chinese Medicine (TCM)-derived bioactive compounds have significant research value in this field. This study aimed to synthesize current preclinical and emerging clinical evidence on the neuroprotective and psychotropic effects of key TCM constituents, with a particular focus on their roles in modulating neuroinflammatory signalling, synaptic plasticity, oxidative balance and stress-related neuroendocrine pathways. A narrative synthesis of experimental and early clinical studies was conducted, emphasizing mechanistic investigations in rodent models and exploratory human trials. Outcomes of interest included inflammatory cytokine expression, inflammasome activation, redox homeostasis, synaptic signalling pathways, neuroendocrine regulation, behavioural performance and translational pharmaceutical considerations. Multiple TCM constituents attenuate microglial activation and inflammasome signalling, suppressing interleukin-1β, interleukin-6 and tumor necrosis factor-alpha through inhibition of nuclear factor κB and NOD-like receptor pyrin domain-containing 3 pathways. These effects restore redox homeostasis, reduce synaptic loss and improve cognitive and behavioural outcomes in animal models. Concurrently, several compounds enhance synaptic resilience by upregulating brain-derived neurotrophic factor and tropomyosin receptor kinase B signalling, activating downstream mechanistic target of rapamycin complex 1 and cyclic adenosine monophosphate response element-binding protein pathways and preserving synaptic proteins. Key agents, including ginsenosides, baicalin and curcumin, have shown translational promise, with small human trials reporting improvements in depressive symptoms, cognitive function and biomarker profiles. Additionally, TCM compounds modulate HPA axis dynamics by attenuating stress-induced corticosterone elevation, restoring glucocorticoid receptor sensitivity and rebalancing monoaminergic and glutamatergic neurotransmission. However, pharmaceutical translation remains limited by challenges related to formulation, dosage standardization and poor oral bioavailability, particularly for flavonoids and saponins. TCM-derived compounds exert multifaceted neuroprotective and psychotropic effects, while successful clinical translation requires strengthened pharmaceutical characterization, standardized dosing strategies and advanced delivery systems such as nanoformulations, phytosomes and standardized granules to enhance bioavailability, reliability and regulatory acceptance. Show less

Epilepsy is generally described as a pathology resulting from an imbalance between excitatory and inhibitory activities. In recent years, neurotrophins have been recognized as key players in the pathophysiology of nervous system diseases. One such neurotrophin, BDNF, and its receptor, TrkB, play critical roles as epileptogenic factors that regulate neuronal hyperexcitability and synaptic plasticity. In this study, we sought to elucidate the exact mechanisms underlying the neuroprotective and antiepileptic effects of pantoprazole. The molecular docking study indicated key interactions of pantoprazole with the TrkB receptor (PDB ID: 4AT3). Furthermore, pantoprazole exhibited notable in vitro TrkB kinase inhibitory activity (IC Show less

(ACR)-induced neurotoxicity, focusing on oxidative stress, endoplasmic reticulum (ER) stress, neuroinflammation, and apoptosis mechanisms. Fifty male Sprague-Dawley rats were divided into five groups: Control, ACR, GA50 +ACR, GA100 +ACR, and GA100. GA (50 and µmg/kg) and ACR (50 mg/kg) were administered intraperitoneally for 14 days. ACR exposure significantly decreased antioxidant enzyme activities (SOD, GSH, GPx, CAT) and increased malondialdehyde (MDA) levels, pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), neuronal nitric oxide synthase (nNOS), and apoptosis-related gene expression (Bax and caspase-3). Histopathological analysis revealed neuronal degeneration and vascular hyperemia, while BDNF, Nrf2, and HO-1 immunoreactivity decreased in the ACR group. GA treatment, particularly at 100 mg/kg, markedly ameliorated these biochemical, molecular, and histopathological alterations. These findings indicate that GA exerts significant neuroprotective effects against ACR-induced brain injury by modulating oxidative stress, ER stress, inflammatory, and apoptotic pathways. Show less

Dementia involves progressive cognitive decline, impairing daily and social activities. As no current drugs can reverse this decline, preventive strategies using functional compounds are gaining attention. Rutin, a flavonoid with neuroprotective and vascular benefits, has limited bioavailability due to poor water solubility. Although enzymatic glycosylation improves its solubility, it contains multiple compounds with differing numbers of sugar units and is not a single compound. To address this, EubioQuercetin®, a novel water-soluble rutin (wsRutin) formulation, was developed using L-arginine and ascorbic acid, without enzymatic processing. Here, we evaluated the neuroprotective effects of quercetin and isorhamnetin, the major metabolites of rutin, and compared the cognitive effects of rutin suspension and wsRutin solution in mice. Quercetin and isorhamnetin suppressed glutamate-, menadione- and H Show less

Buchanania lanzan Spreng. (Anacardiaceae) seeds (BLHA) are the cheaper alternative to almonds used in the confectionery industry. The flour powder of seeds is used as a thickening agent to prepare sauces and flavourings for a batter. The socioeconomic importance of this species lies in its medicinal properties for curing diabetes. The study explored the multifaceted neuroprotective role of BLHA (500 mg/kg) in hyperlipidic high-fat diet streptozotocin (HFD/STZ)-induced type2 diabetic neuropathy (T2DN) rats via glucose metabolism, insulin resistance, and inflammation to mitigate nerve damage. Molecular docking analysis was performed to identify specific molecular targets of bioactive compounds in T2DN pathogenesis. Serum diabetic parameters, such as serum glucose (SG), insulin (SI), total protein (TP), triglycerides (TG), blood urea nitrogen (BUN), creatinine (Cr), HDL-C, and LDL-C, were studied. A strong correlation between HbA1C and insulin resistance assessed by HOMA-IR. Oxidative stress triggers the production of free radicals, so the antioxidant indicators in serum, tissues, and proinflammatory cytokines in the liver, brain, and pancreas were measured in T2DN rats. Effects on neurochemicals, BACE1, Aβ BLHA at 500 mg/kg significantly improved hyperglycemic (SG, SI, HOMA-IR, HbA1C), hepatic (AST, ALT, ALP, TP, TB), dyslipidemic (TC, TG, HDL-C, LDL-C), and kidney function markers (creatinine, BUN) in T2DN rats. BLHA restored oxidative (CAT, GSH, SOD, MDA) and cytokine markers (TNF-α, IL6) in the liver, pancreas, and brain cortex. Oxidative stress-impaired neurotransmitters were alleviated by enhancing cholinesterase (AChE, BChE) and BACE1 activities, and by ameliorating Aβ The multifaceted actions of dietary polyphenols, antioxidants, and antidiabetic compounds (Catechol, 2-Hydroxy-5-methylbenzaldehyde, 8-Octadecenoic acid methyl ester, n-Hexadecanoic acid, 2-hydroxy-1-(hydroxymethyl)ethyl ester, β-Sitosterol, Hexadecenoic acid methyl ester) in BLHA modulated glucose metabolism, restored HOMA-IR, and reduced inflammation by protecting against oxidative stress, as a result, it improved neurotransmission and reduced neuropeptide aggregation in T2DN rats. The dock score of β-sitosterol (AChE: -12.7; BChE: -14.8; IL6: -9.8; and Atp1a3: -13.3 kcal/mol) correlated with the experimental evidence. Show less

This study aimed to investigate the effects of L-borneol on the molecular, biochemical, and histological damage caused by acrylamide (ACR) in the hippocampus of adult male Wistar rats. It also examined the impact of L-borneol on spatial memory and anxiety-like behaviors in these animals. Animals were divided into four groups: control, L-borneol, ACR, and ACR + L-borneol. ACR (25 mg/kg) and L-borneol (50 mg/kg) were administered orally for 21 consecutive days. L-borneol reduced levels of malondialdehyde and nitric oxide, increased glutathione content, and enhanced superoxide dismutase activity in the hippocampus of rats treated with ACR. In addition, L-borneol lowered the expression of pro-inflammatory markers, nuclear factor-κB, and inducible nitric oxide synthase in the hippocampus. It effectively prevented changes in the expression of apoptosis-related genes, which are associated with decreased neuronal death in the cornus ammonis 1 and dentate gyrus regions. Moreover, L-borneol increased the expression of sirtuin 1 (SIRT1), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), brain-derived neurotrophic factor, and alpha 7-nicotinic acetylcholine receptors, while reducing the expression and activity of acetylcholinesterase. Finally, L-borneol improved spatial memory and reduced anxiety-like behaviors. In conclusion, L-borneol enhances behavioral performance in ACR-exposed animals by decreasing oxidative and nitrosative stress, as well as inhibiting inflammation and apoptosis. It appears that the upregulation of the SIRT1/Nrf2/HO-1 signaling pathway and the stimulation of acetylcholine signaling are crucial for mitigating ACR-induced neurotoxicity. Show less

Memantine (Mem), an uncompetitive antagonist of the N-methyl-D-aspartate receptor (NMDAr), has demonstrated neuroprotective effects in preclinical stroke models by reducing excitotoxic damage. However, the efficacy of low acute doses administered during the immediate post-ischemic phase remains insufficiently characterized. Male rats underwent permanent middle cerebral artery occlusion (pMCAO) and received a single intraperitoneal dose of Mem (5 mg/kg) two hours post-occlusion. Neurological deficits were assessed using the modified Neurological Severity Score (mNSS). Infarct area and neuronal preservation were quantified using MAP2 immunohistochemistry. BDNF and PSD95 protein levels were measured by ELISA, and their gene expression was evaluated via RT-PCR. Mem treatment significantly reduced infarct area (p = 0.000029) and attenuated neurological deficits (p < 0.0001). MAP2 immunoreactivity was higher in the Mem-treated group (p = 0.000003), indicating preservation of neuronal structure. BDNF protein levels did not differ between the pMCAO and pMCAO+Mem groups; PSD95 protein and its corresponding DLG4 mRNA were increased in the pMCAO group compared with Sham. In the other groups, levels remained unchanged. Early administration of low-dose memantine confers acute neuroprotection after stroke by reducing tissue damage and preserving neuronal integrity, without affecting ischemia-induced BDNF and PSD95 protein and gene expression. These findings suggest a selective early neuroprotective mechanism and highlight the need for long-term and sex-inclusive studies to further evaluate memantine's therapeutic potential. Show less

Retigabine (RTG) shows notable neuroprotective efficacy in multiple brain injury models; however, its interplay with endoplasmic reticulum stress (ERS) is poorly understood. This study was designed to explore the therapeutic potential of RTG against CRS-induced depression-like behaviors and cognitive deficits in mice and to uncover the associated molecular mechanisms. A depression-like and cognitive impairment model was established in C57BL/6 male mice using chronic restraint stress (CRS). Six-week-old C57BL/6 male mice were randomly assigned to the following groups: control (Con), model (CRS), RTG (10 mg/kg), XE-991 (2 mg/kg) or tunicamycin (Tm, 2 mg/kg). Behavioral tests were conducted to assess depression-like behaviors and cognitive function. Hippocampal neuronal morphology was examined by H&E and immunofluorescence staining, while changes in endoplasmic reticulum stress (ERS)-related signaling pathways were analyzed by Western blot. Retigabine treatment reduced hippocampal neuronal damage and the expression of ERS-related factors (GRP78, CHOP) and the pro-apoptotic factor BAX in CRS-induced mice, while it increased the levels of BDNF. These effects were antagonized by XE-991 and the ERS agonist tunicamycin (Tm). Retigabine may alleviate CRS-induced depressive-like behaviors and cognitive impairment by inhibiting ERS-mediated apoptosis, suggesting its potential as a novel therapeutic strategy for depression. Show less

Parkinson's disease (PD) is a common neurodegenerative disorder involving multiple pathological processes. Bergapten (BeG) exhibits various pharmacological activities, including anti-inflammatory, antioxidant and neuroprotective effects, but its mechanism of action in PD remains unclear. This study aimed to investigate the neuroprotective effects and underlying mechanisms of BeG in PD models. An in vitro neuroinflammation model was established using LPS-treated astrocytes. In-vitro studies demonstrated that BeG counteracted LPS-induced astrocyte activation by reducing the expressions of GFAP, inflammatory mediators (IL-6, TNF-α, IL-1β), and A1 polarization markers. It alleviated ERS (as indicated by reduced levels of GRP78, CHOP) and apoptosis (as shown by changes in Bax, caspase-3) while enhancing Bcl-2. Mechanistically, BeG suppressed LCN2 expression and JAK2/STAT3 phosphorylation, with LCN2 overexpression attenuating its protective effects. In MPTP-treated mice, BeG improved motor function, preserved dopaminergic neurons, and reduced astrocyte activation and A1 polarization. It increased neurotrophic factors (BDNF, GDNF) while decreasing inflammation, ER stress and apoptotic markers. The inhibition of the LCN2/JAK2/STAT3 pathway was consistently observed in both models, suggesting its central role in BeG's neuroprotective mechanism. These findings suggest that BeG exerts neuroprotective effects in PD by inhibiting the LCN2/JAK2/STAT3 signaling pathway, thereby effectively inhibiting astrocyte activation-mediated neuroinflammation and ERS. Show less

Sepsis elevates the risk of depression and cognitive impairment. Glucagon-like peptide-1 (GLP-1) analogues exhibit neuroprotective potential, yet their effects on sepsis-induced depression (SID) remain unelucidated. This study explored whether exenatide (Exe) alleviates depressive-like behaviors and cognitive deficits in a murine SID model. SID mice were intraperitoneally administered exenatide (1 mg/kg/day) or vehicle for 14 days. Behavioral assessments included the Open Field Test, Forced Swimming Test, Tail Suspension Test, Sucrose Preference Test, Morris Water Maze, Novel Object Recognition, Novel Location Recognition, Three-Chamber Social Interaction Test, and IntelliCage system. Murine sepsis clinical scores and Nissl staining evaluated the model behaviorally and histologically. High-performance liquid chromatography quantified hippocampal 5-hydroxytryptamine (5-HT) and dopamine (DA), while enzyme-linked immunosorbent assay measured hippocampal and plasma biomarkers. Chronic exenatide treatment significantly reduced immobility time in the Forced Swimming and Tail Suspension Tests, improved cognitive performance in the Morris Water Maze, enhanced sucrose preference, and boosted novel object/location recognition and social interaction. Exenatide downregulated tumor necrosis factor-α, interleukin-6, and adrenocorticotropic hormone levels, while upregulating 5-HT, DA, phosphorylated cAMP response element-binding protein, and brain-derived neurotrophic factor. Exenatide exerts antidepressant-like and pro-cognitive effects in SID mice, likely via GLP-1 receptor-mediated suppression of hippocampal inflammation and promotion of neuroplasticity. GLP-1 analogues are promising dual-action therapeutics for comorbid depression and cognitive deficits, pending validation in further models and clinical trials. Show less

Neuroinflammation is a central contributor to Huntington's disease (HD) pathogenesis and represents a promising therapeutic target. Laquinimod, an oral immunomodulator with demonstrated neuroprotective effects in preclinical models, has been investigated as a potential treatment for HD. This review critically appraises its preclinical and clinical evidence. A systematic search (January 2025) was conducted in PubMed, Scopus, Embase, Cochrane Library, and Web of Science using terms including "Huntington's disease," "laquinimod," and "quinoline-3-carboxylic acid." Preclinical and clinical studies evaluating laquinimod in HD were included. Due to heterogeneity, findings were synthesized qualitatively. Of 2638 records identified, 10 studies met the inclusion criteria. Preclinical data showed laquinimod improved motor function, reduced neuroinflammation, and promoted myelination, likely via microglial modulation, NF-κB suppression, and increased BDNF expression. Effects on myelin integrity and inflammatory markers were inconsistent. In vitro studies showed limited, variable cytokine modulation in HD patient-derived cells. Clinical trials did not demonstrate significant improvements in motor or functional outcomes, though one study reported minor cognitive and behavioral benefits. Preclinical evidence suggests laquinimod may modulate motor, inflammatory, and myelination pathways in HD; however, clinical evidence shows no meaningful benefit. Data on long-term safety remain limited. Larger, well-designed trials using standardized biomarkers are needed to clarify its therapeutic potential. Show less

Alzheimer's disease (AD) is a progressive disorder that affects the brain and leads to cognitive decline and memory loss, with postmenopausal women being unduly affected. Estrogen is believed to exert neuroprotective effects by influencing amyloid-beta accumulation, tau hyperphosphorylation, oxidative stress, synaptic function, neuroinflammation, and brain-derived neurotrophic factor (BDNF) signalling. This review examines the role of estrogen in AD pathogenesis among postmenopausal women. A systematic literature search was conducted using PubMed, Scopus, and Web of Science. Keywords included "estrogen", "Alzheimer's disease", "neuroprotection", "amyloid-beta," and "BDNF." Inclusion criteria were peer-reviewed studies from the past 10 years focusing on estrogen's effects on AD mechanisms, neurobiology, and therapeutic relevance. Articles were screened by title and abstract. Followed by a full-text review to ensure methodological rigour and relevance. Evidence indicates that estrogen reduces amyloid beta burden, inhibits tau phosphorylation, mitigates oxidative stress, preserves synaptic connectivity, and suppresses neuroinflammation. Estrogen also modulates ApoE-linked lipid metabolism and enhances BDNF signalling, supporting neuronal survival and cognitive resilience. Declining estrogen after menopause increases vulnerability to AD. Understanding estrogen's neuroprotective mechanisms may support targeted therapeutic strategies. Hormone replacement therapy (HRT) and selective estrogen receptor modulators (SERMs) show potential, but further research is needed to optimise timing, dosage, and patient selection in postmenopausal AD prevention and management. Show less

The vital role of brain-derived neurotrophic factor (BDNF) in neuronal development, synaptic plasticity, and neuroprotection has been explored for decades. Therefore, the expression, processing, and signalling activities of this neurotrophin, which is reliant upon TrkB and p75NTR receptors, have been well characterised in both health and disease. This review summarises the latest findings on BDNF dysregulation in neuropathologies. Indeed, across diseases of both the central and peripheral nervous systems, BDNF signalling is frequently disrupted, contributing to neuronal dysfunction and degeneration. Consequently, through direct or indirect enhancement of its expression and/or function, BDNF has proved to be a promising therapeutic target across many neurological conditions. However, the complexity of its regulation and interaction with several different receptors underpins the need for further research to deepen our understanding of BDNF disruption in neuropathologies and to achieve its therapeutic potential. Show less

Intracerebral hemorrhage (ICH) is a destructive cerebrovascular disease, whose secondary injury can trigger severe neuroinflammatory responses. Resolvin D1 (RvD1), as an endogenous specific pro-resolving mediator, has been demonstrated to possess significant anti-inflammatory effects. However, how brain networks relate to RvD1 biosynthesis and the therapeutic potential of RvD1 in post-hemorrhagic repair processes within the brain remain unclear. Serum RvD1 levels were measured at admission and discharge in 40 ICH patients, and their correlation with neurological functional outcomes was analyzed. Combining neuroimaging and Mendelian randomization, we investigated the association between brain network integrity and genetically predicted plasma RvD1 levels. Network pharmacology identified key targets, and an oxyhemoglobin-induced BV2 microglial model validated RvD1's BDNF-dependent anti-inflammatory and anti-apoptotic effects. Serum RvD1 levels decreased from admission to discharge during recovery, with significant correlation between its changes and neurological improvement. Neuroimaging and MR analysis revealed that brain network integrity is significantly associated with genetically predicted plasma RvD1 levels, partially explaining interindividual prognostic variation. Mechanistically, RvD1 modulates microglial metabolism, alleviates oxidative stress, and promotes anti-inflammatory polarization involving the BDNF/AKT signaling network. Genetically predicted plasma RvD1 levels correlate with macro-level brain network integrity while simultaneously promoting micro-level neural repair. This approach overcomes limitations of previous single-pathway or static indicator studies, offering novel biomarkers and intervention strategies with predictive and therapeutic potential for ICH. Show less

To investigate the effect of pterostilbene (PTE), a natural dimethyl ether analog of resveratrol with higher bioavailability, on cognitive recovery after cerebral ischemia reperfusion (IR) injury and its potential mechanisms. Mice were subjected to middle cerebral artery occlusion and assigned to Sham, IR, PTE+IR, and PTE+Zinc Protoporphyrin (ZnPP)+IR groups. Cognitive function was assessed using the Morris water maze. Cerebral infarct volume was evaluated by 2,3,5-triphenyltetrazolium chloride (TTC) staining, and neuronal apoptosis was determined via TUNEL assay. The protein levels of postsynaptic density protein 95 (PSD-95), phosphorylated cAMP response element-binding protein (p-CREB), brain-derived neurotrophic factor (BDNF), and histone deacetylases (HDACs) in the hippocampus were measured by western blot. PTE treatment significantly reduced cerebral infarct volume, alleviated cognitive deficits, and inhibited neuronal apoptosis in the hippocampus. At the molecular level, PTE up-regulated the expression of PSD-95, p-CREB, and BDNF, while down-regulating HDAC (1, 2, 3, 4, 7) levels. The beneficial effects of PTE were partially reversed by the HO-1 inhibitor ZnPP. PTE ameliorates cognitive impairment induced by cerebral IR injury, potentially through activating the BDNF/CREB pathway and inhibiting HDAC expression. This suggests PTE as a promising neuroprotective agent for post-stroke cognitive recovery. Show less

Chemotherapy-induced peripheral neuropathy (CIPN) remains a major unmet challenge in oncology, affecting treatment adherence and patient quality of life. Despite its prevalence, reliable predictive biomarkers and targeted neuroprotective strategies remain elusive. This study integrates clinical data, whole-genome sequencing, and translational research to identify genetic determinants of CIPN susceptibility and validate therapeutic approaches. Through comprehensive analysis of patients with colorectal cancer, including neurophysiological evaluations and CIPN-specific quality-of-life assessments, we identified the Show less

Luteolin, a flavonoid naturally present in a variety of fruits, vegetables, and medicinal plants, has been recognized as a potentially effective neuroprotective nutraceutical because of its remarkable anti-inflammatory, antioxidant, and neurotrophic properties. Increasing evidence suggests that neuroinflammation and oxidative stress are major contributors to cognitive decline and neuronal degeneration in several prominent neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and multiple sclerosis (MS). Luteolin significantly inhibits microglial activation, reduces pro-inflammatory cytokine production, modulates the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, and enhances Nrf2-mediated antioxidant mechanisms. Furthermore, it promotes synaptic plasticity through brain-derived neurotrophic factor (BDNF)-associated pathways and mitigates the aggregation of pathological proteins, including Aβ, tau, α-synuclein, and mutant huntingtin. Preclinical studies consistently demonstrate substantial improvements in cognitive function, motor performance, demyelination, and neuronal viability in models of AD, PD, MS, and HD. Preliminary clinical observations also indicate prospective advantages for cognitive function, regulation of inflammatory responses, and alleviation of symptoms, particularly concerning AD and MS. Notwithstanding these encouraging outcomes, obstacles persist due to luteolin's restricted bioavailability, ideal dosing parameters, and the translational discrepancies between experimental models and human pathophysiological conditions. In summary, luteolin emerges as a noteworthy candidate for nutraceutical-oriented approaches designed to alleviate neuroinflammation and cognitive deterioration in the context of neurodegenerative diseases. Show less